The dihydrochloride salt of mitoxantrone is an anthraquinone derivative having the chemical name 1,4-dihydroxy-5, 8-bis[[2-[(2-hydroxyethyl)amino]ethyl]-amino]9,10-anthraquinone or its hydrochloride of the formula ##STR1## Empirical formula: C.sub.22 H.sub.28 N.sub.4 O.sub.6.2 HCl
Mitoxantrone or its salt novantrone exhibit antineoplastic, antiviral, antiprotozoal and immunomodulating properties. The compound is of great benefit as a cytostatic, in particular in the therapy of carcinoma of the breast, malignant lymphomas, acute leukemias, primary liver cell carcinoma and ovarian carcinoma.
Aqueous solutions of this compound have gained acceptance as a pharmaceutical formulation. The stability of mitoxantrone in aqueous solution is, however, quite limited. The compound is subject to oxidative decomposition if measures are not taken to slow this degradation or, better yet, to prevent it. Metal ions in particular, even in very low concentrations, can be used to increase this trend. This degradation can also be counteracted by the use of antioxidants.
European patent No. B-0 236,822 describes a preparation which is stabilized by a combination of a sodium metabisulphite, antioxidant at a specific pH, and disodium edetate as chelating agent, and glycine. Although this preparation is stable, it is unsatisfactory due to side effects of the additives. The use of sodium metabisulphite is disadvantageous even if it is very effective as a stabilizer.
Mitoxantrone solutions are commercially available. With a sulfite additive hypersensitivity reactions with in some cases serious side effects have been reported in man. When using preparations which contain sulfite in the concentrations customarily employed, life-threatening complications have been mentioned in the case of asthmatics with sulfite sensitivity.
The use of a metal ion-binding combination of at least two chelating agents represent additional constituents for such preparations.
A strongly acidic pH of less than 3 also has a disadvantageous effect, both on the tolerability and on the stability of the solutions, as reported by Wang, Da-Peng; Liang, Gow-Zaw; Tu, Yu-Hsing; Stability of mitoxantrone hydrochloride in solution, Drug Development and Industrial Pharmacy, 20(11), 1895-1903 (1994).